Gene Variant, Smoking Combine to Increase Macular Degeneration Risk

Tuesday, March 7, 2006

Durham, N.C. An interaction between cigarette smoking and a susceptibility gene, called LOC387715, greatly increases the risk of developing age-related macular degeneration (AMD), Duke University Medical Center and Vanderbilt University Medical Center have found.

The combination of these factors accounts for as many as one third of the cases of AMD, the researchers estimated. The study represents one of the first examples of an interaction between genetic and environmental factors in the development of a common disease, they said.

The researchers said their findings emphasize the importance of genetic factors in the onset of AMD. They also said that the research has the potential to reduce the impact of the version, or allele, of the LOC387715 gene on the aging population by public health efforts, such as smoking prevention and cessation programs.

The results of the Duke research will appear March 6, 2006, in the online edition of the American Journal of Human Genetics, to be published in print in the May issue of the journal. The work was supported by the National Eye Institute of the National Institutes of Health.

"The most exciting aspect of this research is that it is the combination of the gene and smoking that really puts you at risk," said Margaret Pericak-Vance, Ph.D., director of the Duke Center for Human Genetics and senior author of the report. "We demonstrate, for the first time, that a gene variant coupled with a modifiable lifestyle factor such as cigarette smoking confers a significantly higher risk of AMD than either factor alone."

AMD is the most common cause of visual impairment and legal blindness in older Americans. The condition leads to blindness by progressively destroying the central portion of the retina, an area known as the macula. Today, ten to fifteen million people in the United States have AMD, and that number is expected to double as the baby boomer generation ages.

"Several environmental factors have been implicated in AMD," said Jonathan Haines, Ph.D., of Vanderbilt Center for Human Genetics Research, a co-author in the study. "The strongest effect comes from smoking, which is why we included it in this study. Another risk factor is family history, which led us to look for the genes involved."

The study was conducted in 1,001 people with all forms of AMD and 394 unrelated healthy controls. The team evaluated 185 variations in the DNA sequences of genes found in a particular region of the genome that other genetic studies had implicated in susceptibility to AMD.

The researchers found that 42 percent of the chromosomes of people with AMD, compared with 26 percent of controls, had a specific sequence variant of LOC387715 statistically associated with the highest risk of developing the disease. Their analysis showed that in non-smokers, the genetic variant confers a two-fold increase in AMD risk. However, in smokers who carry the genetic variant, the risk is increased about eight-fold, compared to non-smokers without the variant. The actual function of the gene in the visual system is unknown, noted the researchers.

"We found that the gene variant increases AMD risk even if a person does not smoke," said Silke Schmidt, Ph.D., first author of the study. "If the person does smoke and has a bad genotype, the risk increases dramatically. This suggests that gene carriers can reduce their AMD risk substantially by not smoking."

The new study of LOC387715 represents discovery of the second major susceptibility gene for AMD. An earlier study by this group and others identified the first major genetic risk factor for the disease, a gene called complement factor H (CFH). CFH is believed to play a role in the regulation of the immune system.

The joint effect of the two variants and smoking may be responsible for up to 61 percent of all cases of AMD, said the researchers. The finding might also give those at greatest risk for developing the condition a chance to undergo therapies or quit smoking to slow the progression of the disease, they said.

Once AMD reaches the advanced stage, no treatment can prevent or restore vision loss. However, people can delay and possibly prevent AMD from progressing. They can take a high-dose formulation of antioxidants and zinc to significantly reduce the risk of advanced AMD and its associated vision loss. Because obesity is a risk factor, weight reduction by maintaining a healthy diet and exercising can also reduce the risk of developing AMD.

For the more severe form, people with AMD can undergo treatments including laser surgery and drug injections to seal the leaking blood vessels, halting the damage they can inflict upon the retina. In laser surgery a high energy light beam is aimed directly onto the new blood vessels and destroys them, preventing further loss of vision. An alternative treatment is the injection of a drug to block the growth of abnormal new blood vessels, again slowing vision loss from AMD.

The discovery gives researchers a chance to further understand AMD, explained Pericak-Vance. The hope is that this information could ultimately lead to better treatments and prevention for those afflicted with the disease.
"You can not change your genetics," explained study co-author Eric Postel, M.D., an ophthalmologist at the Duke Eye Center, "but there are things you can do to reduce your risk. You can change your diet, take vitamins, and stop smoking."

Collaborators on the study include Michael Hauser, William Scott, Paul Gallins, Frank Wong and Yu Sarah Chen, of the Duke Center for Human Genetics; Kylee Spencer, Nathalie Schnetz-Boutaud, and Anita Agarwal, of the Vanderbilt University Medical Center.